Human Genetics Training Program

The overall goal of our research is to dissect fundamental cellular processes relevant to human health and disease, using yeast and mammalian cell biology, biochemistry, and high-throughput genomic approaches. One project in the laboratory focuses on a rare premature aging disorder, Hutchinson-Gilford progeria syndrome (HGPS), which results from a mutation in the gene (LMNA) encoding the nuclear scaffold protein lamin A.  Children with HGPS exhibit profound characteristic of aging, including hair loss, skin and bone defects, and heart disease.  The mutant form of lamin A in HGPS patient cells is persistently modified by the lipid farnesyl (an aberrant situation, since normally a proteolytic cleavage removes the farnesylated C-terminal tail of lamin A during biogenesis).  Excitingly, we have found that a particular class of anti-cancer drugs called the farnesyl transferase inhibitors (FTIs) can dramatically block the nuclear abnormalities characteristic of HGPS fibroblasts and thus may be useful to treat HGPS.  We are currently examining the basic cell biology of lamin A processing, molecular mechanisms of lamin A toxicity in HGPS, and the link between HGPS and normal aging.

Another project in our laboratory focuses on ER quality control (ERQC), a process which ensures that misfolded secretory and membrane proteins, such as the mutant cystic fibrosis channel protein, are retained in the endoplasmic reticulum and subsequently undergo degradation by the ubiquitin-proteasome system.  Our goal is to identify the core cellular machinery that mediates ERQC.  To do so, we are using misfolded proteins as “bait” in a variety of genome-wide yeast screens designed to uncover the eukaryotic ERQC machinery.  Ultimately, a detailed understanding of the cellular players that mediate this process will facilitate development of treatments for ERQC-based diseases such as cystic fibrosis.